WO1995014483A1 - Composition comprising sulcralfate and an antimicrobial agent/ion-exchange resin complex - Google Patents
Composition comprising sulcralfate and an antimicrobial agent/ion-exchange resin complex Download PDFInfo
- Publication number
- WO1995014483A1 WO1995014483A1 PCT/EP1994/003803 EP9403803W WO9514483A1 WO 1995014483 A1 WO1995014483 A1 WO 1995014483A1 EP 9403803 W EP9403803 W EP 9403803W WO 9514483 A1 WO9514483 A1 WO 9514483A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- ion
- drug
- antimicrobial agent
- exchange
- helicobacter pylori
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/245—Bismuth; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/58—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
- A61K47/585—Ion exchange resins, e.g. polystyrene sulfonic acid resin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Definitions
- This invention relates to the treatment of gastrointestinal disorders and pharmaceutical compositions for use therein. More particularly the invention relates to pharmaceutical compositions containing an antimicrobial agent active against Helicobacter pylori and their use in the treatment of gastrointestinal disorders associated with Helicobacter pylori infection.
- Helicobacter pylori (formerly known as Campylobacter pyloridis) is a spiral-shaped Gram-negative organism which resides beneath the mucus layer of the stomach. Many recent studies have shown an association between the presence of H. pylori in the gastric mucosa and histologically confirmed gastritis.
- the organism may be a pathogen which causes, or at least exacerbates, gastritis, and may also be important in the aetiology of peptic ulceration.
- Reviews on the state of the art include those by CAM. McNulty in J. Infection, 1986, 13, 107-113, and by CS. Goodwin et al. in J. Clin. Pathol., 1986, 39, 353-365.
- H.pylori is known to be susceptible to a large number of antimicrobial agents in vitro. It has been shown that treatment of gastritis with antimicrobial agents, for example ⁇ -lactam antibiotics such as amoxycillin, or bismuth salts, leads to eradication of the associated H.pylori organisms in vivo.
- antimicrobial agents for example ⁇ -lactam antibiotics such as amoxycillin, or bismuth salts
- GB 2 243 549 A (Reckitt & Colman) claims the use of the non-antibiotic antimicrobial agent triclosan for the preparation of a medicament for the treatment of gastrointestinal disorders associated with Helicobacter pylori infection.
- GB 2 243 549 A discloses the in vitro testing of 11 antimicrobial compounds in addition to triclosan versus Helicobacter pylori. based on methods described by McNulty et al. (Antimicrobial Agents & Chemotherapy, 28, 837- 838, 1985).
- Beecham discloses a range of antimicrobial agents, including cationic antimicrobial agents, benzene derivatives, phenols, amines and certain naturally occuring substances as having useful activity against Helicobacter pylori.
- Gastric sustained release compositions are also obtained by formulation of medicaments so as to produce a floating raft within the stomach.
- Alginate substances are particularly suitable for the production of floating alginate rafts.
- Bioadhesive agents constitute a further example; they are able to prolong residence time by adhesion to mucus membranes and thus ensure an optimal contact with the absorbing surface.
- Many different types of bioadhesive materials can be used in the design of controlled drug delivery systems.
- GB 2 243 549 A discloses a medicament for the treatment of gastrointestinal disorders associated with Helicobacter pylori comprising triclosan which may be formulated as a gastric sustained release composition having prolonged residence time within the stomach and continuously releasing triclosan during that time.
- Triclosan compositions formulated so as to produce floating alginate rafts within the stomach, or as muco-adherent coated granules or spheroids, are identified as suitable sustained release compositions.
- Sucralfate is a basic aluminium sulphate sucrose complex having ulcer healing and buffering properties. Sucralfate has been shown to act by forming a bioadhesive gel structure under aqueous acid conditions which is believed to provide a local protective barrier. The preparation and use of sucralfate is described in for example US Patent No. 3, 432, 489 and "The Merck Index" 11th Edition (1989), page 1400, Entry No. 8853.
- EP-A-0 403 048 (Warner-Lambert) describes medicated compositions comprising sucralfate and a therapeutically effective amount of a medicament which is a) substantially water insoluble, or b) a mixture of a water-soluble medicament and a release-delaying material which on admixture forms a substantially water-insoluble medicament.
- Antibacterials are listed as one of several types of therapeutic agent where the medicament is an antiulcer medicament.
- WO 92/18111 also discloses compositions in which the antimicrobial agent active against Helicobacter pylori is coformulated with one or more substances providing a sustained release and/or prolonged retention time of the antimicrobial agent in the stomach. Sucralfate is identified as one such substance.
- WO 92/11871 (Allergan Inc.) describes a stable suspension for controlled delivery of a pharmaceutical compound comprising drug loaded ion-exchange resin particles incorporated in an erodible polymeric matrix to form microparticulates. When suspended in a fluid medium the encapsulating matrix shields the drug loaded ion- exchange resin from solvent interaction. When administered to a target site, typically characterised by rapid fluid turnover or drainage, erosion of the polymer matrix and release of the pharmaceutical compound is initiated.
- the present invention provides a pharmaceutical composition comprising sucralfate and a drug/ion-exchange complex formed between a water- soluble antimicrobial agent having activity against Helicobacter pylori and a cationic ion-exchange resin.
- a composition comprising sucralfate and a drug/ion-exchange complex formed between a water-soluble antimicrobial agent having activity against Helicobacter pylori and a cationic ion-exchange resin for use in therapy also forms part of the present invention.
- the invention also extends to the use of a pharmaceutical composition comprising sucralfate and a drug/ion-exchange complex formed between a water- soluble antimicrobial agent having activity against Helicobacter pylori and a cationic ion-exchange resin for the manufacture of a medicament for the treatment of gastric disorders associated with Helicobacter pylori infection.
- Suitable water-soluble antimicrobial agents for use in compositions of the present invention include cetyl pyridinium chloride (CPC), water-soluble forms of chlorhexidine, in particular chlorhexidine hydrochloride, bismuth compounds such as bismuth aluminate, bismuth carbonate, bismuth subcitrate, bismuth subgalate and bismuth subsalicylate, and miconazole.
- CPC cetyl pyridinium chloride
- chlorhexidine hydrochloride bismuth compounds such as bismuth aluminate, bismuth carbonate, bismuth subcitrate, bismuth subgalate and bismuth subsalicylate, and miconazole.
- a wide range of cationic ion-exchange resins is potentially available to form drug-resin complexes for use in the present invention.
- Suitable pharmaceutically acceptable cationic ion-exchange resins are commercially available and include a range of synthetic cationic ion-exchange resins with different polymeric matrices which may be cross-linked.
- a synthetic cationic ion-exchange resin may for example be a polymer of styrene, or acrylic or methacrylic acid, and the resin may derive its exchange activity from either weakly or strongly acidic groups such as carboxylic acid or sulphonic acid groups.
- Ion-exchange resins particularly suitable for use in compositions of the invention include strongly cationic resins having sulphonic acid groups on a polystryene polymer matrix, which resins are suitably cross-linked, preferably by a divinyl or polyvinyl compound such as divinylbenzene.
- the proportion of cross-linking may vary from 1 to 20%, suitably from 1 to 12%, and preferably from 7 to 9% by weight cross-linking.
- Suitable resins are those commercially available under the trade names Amberlite and Duolite from Rohm and Haas Co. and Dowex from the Dow Chemical Co..
- the resin may be in either acid form or in the form of a salt with an alkali metal such as sodium or potassium.
- the water-soluble antimicrobial agent is a pharmaceuticaly acceptable acid addition salt
- the chosen resin will be in its salt form.
- the water-soluble antimicrobial agent is presented as a free base, the resin will be in its acid form.
- Examples of drug-resin complexes for use in the present invention are those formed between CPC or chlorhexidine HC1 and the sodium form of a sulphonated styrene-divinylbenzene resin, for example Amberlite IRP-69, or the potassium form of a methacrylic acid-divinylbenzene resin, for example Amberlite LRP-88.
- a further example is that formed between miconazole and a methacrylic acid-divinybenzene resin in the free acid form, for example Amberlite IRP-64.
- the scope of invention is not limited to any particular ratio of the antimicrobial agent to ion-exchange resin. It has however been found that optimal absorption and release of antimicrobial agent is achieved when the antimicrobial agent content of the drug-resin complex is up to 10% by weight, suitably between 0.001% and 10% by weight and preferably between 0.001% and 2% by weight.
- the particle size of the ion-exchange resin influences not only the difiiision rate of the antimicrobial agent from the drug-resin complex but also the retention time of the resinate 7er se in the stomach.
- a number of commercially available ion-exchange resins have particle size distributions which favour prolonged gastric residence times and, unless otherwise indicated by the requirements of particular formulation types, these are preferred.
- Drug preparations based on ion-exchange complexes wherein the resinate particle size is greater than about 120 ⁇ m are known to impart a gritty texture which renders them unpalatable if formulated as liquid suspensions or as chewable tablets. Accordingly, for these formulation types, resinates containing a significant proportion of particle sizes above 120 ⁇ m are contra-indicated, in order to provide a product for oral consumption having good mouth feel. Formulation types such as swallow- tablets, lozenges or pills are not however constrained with respect to particle size for reasons of mouth feel. It is however generally preferred to use a resinate with a maximum particle size no greater than 120 ⁇ m and particularly preferred to use a resinate with a maximum particle size no greater than 65 ⁇ m.
- Adsorption of antimicrobial agent onto the ion-exchange resin may be carried out by standard procedures well known in the art, for example as described in US 2,990,332.
- a commercially available ion-exchange resin may be added directly to a solution of the antimicrobial agent in an appropriate solvent.
- Pre ⁇ conditioning of ion-exchange resins prior to complex formation may be desirable in order to remove any potentially toxic extractibles and/or to facilitate easier processing and analysis of the resulting resinate.
- the dose level of the antimicrobial agent may be selected according to the potency of the drug on a weight basis.
- a suitable dosage level for CPC ranges from about 0.01 mg to aboutl mg per dosage form, typically from about 0.05 mg to about 0.2 mg.
- the antimicrobial agent is chlorhexidine, it may be present in an amount from about 0.01 mg to about 0.3mg per dosage form, typically from about 0.05mg to about 0.2 mg.
- a suitable dosage range is about 0.01 mg to about 0.3 mg per dosage form, typically from about 0.02 mg to about 0.1 mg.
- Sucralfate is suitably present in an amount from about 100 mg to 1000 mg per dosage form, typically from about 300 mg to 800 mg, for example 500 mg.
- Compositions for use in the present invention may also contain one or more pharmaceutically acceptable carriers or excipients.
- Compositions may be formulated for oral administration in solid or liquid form, for example as tablets, capsules, lozenges, granules, powders, suspensions or dispersions. Granules and powders may be ingested directly, or alternatively dispersed in water or other suitable vehicles prior to administration.
- Capsules may be of the hard or soft gelatin type, including chewable soft gelatin capsules.
- compositions may be formulated using conventional carriers or excipients and well established techniques.
- Compositions may for example contain preservatives, buffering agents, suspending agents, flavourings, bulking agents, binders, adhesives, lubricants, disintegrants, colouring agents, sweeteners, adsorbents, thickeners and diluents appropriate to their form.
- the present invention includes a pharmaceutical composition
- a pharmaceutical composition comprising sucralfate and a drug/ion-exchange complex formed between a water- soluble antimicrobial agent having activity against Helicobacter pylori and a cationic ion-exchange resin, further comprising a pharmaceutically acceptable carrier.
- the invention also provides a method of treatment of gastric disorders associated with Helicobacter pylori infection comprising administering to a sufferer an effective amount of a pharmaceutical composition comprising sucralfate and a drug/ion-exchange complex formed between a water-soluble drug having activity against Helicobacter pylori and a cationic ion-exchange resin.
- the invention provides a pharmaceutical composition for use in the treatment of gastric disorders which comprises sucralfate and a drug/ion- exchange complex formed between a water-soluble antimicrobial agent having activity against Helicobacter pylori and a cationic ion-exchange resin.
- Example 1 illustrates tablet dosage forms. Tablet formulations may be swallowed for dispersal in the stomach, chewed in the mouth or dispersed in water before consumption.
- the Example describes the quantity (in mg) of the representative components in a single dosage form.
- the antimicrobial agent and ion-exchange resin are combined in the conventional manner to produce a drug/ion-exchange resinate.
- the resinate and sucralfate are blended along with conventional ingredients as appropriate, such as tabletting aids, fillers and palatability aids and the blend is tabletted on a conventional machine.
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP95901388A EP0730464A1 (en) | 1993-11-27 | 1994-11-16 | Composition comprising sulcralfate and an antimicrobial agent/ion-exchange resin complex |
AU10653/95A AU1065395A (en) | 1993-11-27 | 1994-11-16 | Composition comprising sulcralfate and an antimicrobial agent/ion-exchange resin complex |
JP7514807A JPH09505573A (en) | 1993-11-27 | 1994-11-16 | Composition comprising sucralfate and a composite of antibacterial agent / ion exchange resin |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB939324409A GB9324409D0 (en) | 1993-11-27 | 1993-11-27 | Novel composition |
GB9324409.3 | 1993-11-27 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1995014483A1 true WO1995014483A1 (en) | 1995-06-01 |
Family
ID=10745801
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP1994/003803 WO1995014483A1 (en) | 1993-11-27 | 1994-11-16 | Composition comprising sulcralfate and an antimicrobial agent/ion-exchange resin complex |
Country Status (6)
Country | Link |
---|---|
EP (1) | EP0730464A1 (en) |
JP (1) | JPH09505573A (en) |
AU (1) | AU1065395A (en) |
GB (1) | GB9324409D0 (en) |
WO (1) | WO1995014483A1 (en) |
ZA (1) | ZA949377B (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5595977A (en) * | 1993-10-27 | 1997-01-21 | Dumex-Alpharma A/S | Salts of amino glycosides |
FR2956322A1 (en) * | 2010-02-17 | 2011-08-19 | Urgo Lab | USE OF SYNTHETIC POLYSULFATE OLIGOSACCHARIDES AS DETERSION AGENTS OF A WOUND. |
CN113274404A (en) * | 2020-06-28 | 2021-08-20 | 天翊生物医药科技(天津)有限公司 | New application of medical adsorption resin and helicobacter pylori eliminating medicine |
CN116098863A (en) * | 2023-03-20 | 2023-05-12 | 广东逸舒制药股份有限公司 | Sulfosamine oral suspension and preparation method thereof |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050244367A1 (en) * | 2004-05-03 | 2005-11-03 | Ilypsa, Inc. | Phospholipase inhibitors localized in the gastrointestinal lumen |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1220818A (en) * | 1967-10-31 | 1971-01-27 | Mar Pha Soc D Etude Et D Expl | New medicinal composition |
US4252790A (en) * | 1974-10-23 | 1981-02-24 | Interx Research Corporation | Method for treating gastric ulcer-prone patients |
GB2218333A (en) * | 1988-05-11 | 1989-11-15 | Glaxo Group Ltd | Ranitidine adsorbates |
EP0403048A2 (en) * | 1989-06-14 | 1990-12-19 | Warner-Lambert Company | Medicated compositions containing sucralfate and processes for their production |
WO1992018111A2 (en) * | 1991-04-15 | 1992-10-29 | Smithkline Beecham Plc | Pharmaceutical composition for the treatment of gastritis |
WO1993024124A1 (en) * | 1992-05-26 | 1993-12-09 | Smithkline Beecham Plc | Compositions based on histamine h2-receptor antagonists and cationic exchangers complexes |
-
1993
- 1993-11-27 GB GB939324409A patent/GB9324409D0/en active Pending
-
1994
- 1994-11-16 WO PCT/EP1994/003803 patent/WO1995014483A1/en not_active Application Discontinuation
- 1994-11-16 AU AU10653/95A patent/AU1065395A/en not_active Abandoned
- 1994-11-16 EP EP95901388A patent/EP0730464A1/en not_active Withdrawn
- 1994-11-16 JP JP7514807A patent/JPH09505573A/en active Pending
- 1994-11-25 ZA ZA949377A patent/ZA949377B/en unknown
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1220818A (en) * | 1967-10-31 | 1971-01-27 | Mar Pha Soc D Etude Et D Expl | New medicinal composition |
US4252790A (en) * | 1974-10-23 | 1981-02-24 | Interx Research Corporation | Method for treating gastric ulcer-prone patients |
GB2218333A (en) * | 1988-05-11 | 1989-11-15 | Glaxo Group Ltd | Ranitidine adsorbates |
EP0403048A2 (en) * | 1989-06-14 | 1990-12-19 | Warner-Lambert Company | Medicated compositions containing sucralfate and processes for their production |
WO1992018111A2 (en) * | 1991-04-15 | 1992-10-29 | Smithkline Beecham Plc | Pharmaceutical composition for the treatment of gastritis |
WO1993024124A1 (en) * | 1992-05-26 | 1993-12-09 | Smithkline Beecham Plc | Compositions based on histamine h2-receptor antagonists and cationic exchangers complexes |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5595977A (en) * | 1993-10-27 | 1997-01-21 | Dumex-Alpharma A/S | Salts of amino glycosides |
FR2956322A1 (en) * | 2010-02-17 | 2011-08-19 | Urgo Lab | USE OF SYNTHETIC POLYSULFATE OLIGOSACCHARIDES AS DETERSION AGENTS OF A WOUND. |
WO2011101594A1 (en) * | 2010-02-17 | 2011-08-25 | Laboratoires Urgo | Use of synthetic polysulphated oligosaccharides as cleaning agents for a wound |
FR2976082A1 (en) * | 2010-02-17 | 2012-12-07 | Urgo Lab | METHOD FOR DETERMINING THE DEGRADATION ACTIVITY OF THE FIBRIN MATRIX OF A DETERSION AGENT |
US8940325B2 (en) | 2010-02-17 | 2015-01-27 | Laboratories Urgo | Use of synthetic polysulphated oligosaccharides as cleaning agents for a wound |
CN113274404A (en) * | 2020-06-28 | 2021-08-20 | 天翊生物医药科技(天津)有限公司 | New application of medical adsorption resin and helicobacter pylori eliminating medicine |
CN116098863A (en) * | 2023-03-20 | 2023-05-12 | 广东逸舒制药股份有限公司 | Sulfosamine oral suspension and preparation method thereof |
CN116098863B (en) * | 2023-03-20 | 2023-08-29 | 广东逸舒制药股份有限公司 | Sulfosamine oral suspension and preparation method thereof |
Also Published As
Publication number | Publication date |
---|---|
JPH09505573A (en) | 1997-06-03 |
ZA949377B (en) | 1995-11-06 |
EP0730464A1 (en) | 1996-09-11 |
AU1065395A (en) | 1995-06-13 |
GB9324409D0 (en) | 1994-01-12 |
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